WELCOME to Review
of Ophthalmology's Retina
Online e-newsletter. Each month, Medical Editor Philip Rosenfeld,
MD, PhD, and our editors provide you with this timely and easily
accessible report to keep you up to date on important information
affecting the care of patients with vitreoretinal disease.

In these two randomized, double-masked, active-controlled, Phase III trials, investigators sought
to determine the efficacy and safety of intravitreal aflibercept in patients with
neovascular age-related macular degeneration (AMD) during a second year of variable dosing after
a first-year fixed-dosing period.

Participants consisted of 2,457 patients with neovascular AMD. From baseline to week 52, they
received 0.5 mg intravitreal ranibizumab every four weeks (Rq4), 2 mg aflibercept every four
weeks (2q4), 0.5 mg aflibercept every four weeks (0.5q4), or 2 mg aflibercept every eight weeks
(2q8) after three monthly injections. During weeks 52 through 96, patients received their
original dosing assignment using an as-needed regimen with defined retreatment criteria and
mandatory dosing at least every 12 weeks. Main outcome measures were the proportion of eyes at
week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline);
change from baseline in BCVA.

According to the investigators, proportions of eyes maintaining BCVA across treatments were
94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. They observed that mean
BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of
eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6%
to 54.4%), and more 2.q.4. eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference
of 10.4% [95% confidence interval {CI}, 4.9 to 15.9] and 9.0%
[95% CI, 3.0 to 15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over
96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4,
and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the
2q4 and 2q8 groups versus the Rq4 group (differences of –0.64 [95% CI, –0.89 to
–0.40] and –0.55 [95% CI, –0.79 to –0.30]; p<0.0001,
post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration–defined
arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline
to week 96.

All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA
loss at 96 weeks, the investigators concluded. The 2q8 aflibercept group was similar to ranibizumab
in visual acuity outcomes during 96 weeks, but with an average of five fewer injections. Small losses
at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of
losses commonly observed with variable dosing.

To characterize preinjection intraocular pressure (IOP) in eyes receiving monthly
ranibizumab versus sham or verteporfin photodynamic therapy (PDT) for age-related
macular degeneration (AMD), this post hoc analysis of IOP data from two Phase III
clinical trials, the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab
in the Treatment of Neovascular AMD (MARINA) and the Anti-VEGF Antibody for the Treatment
of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial, was conducted.

Participants consisted of all safety-evaluable patients who received one or more injections of sham
or PDT or of ranibizumab and had one or more post baseline IOP measurements recorded for the study
eye. Preinjection IOP measurements for study eyes (n=1,125) and fellow eyes in MARINA and ANCHOR
at baseline and at each monthly visit through month 24 were analyzed. Endpoints evaluated were
maximum preinjection IOP during the 24-month treatment period; any occurrence of absolute
preinjection IOP of 21 mmHg or more, 25 mmHg or more or 30 mmHg or more; any occurrence of IOP
increase of 6 mmHg or more, 8 mmHg or more or 10 mmHg or more from baseline; any combination of
IOP increase of 6 mmHg or more or 8 mmHg or more from baseline with concurrent absolute preinjection
IOP of 21 mmHg or more or 25 mmHg or more; glaucoma-related adverse events; new glaucoma
medications used for 45 days or more; and glaucoma filtration or laser surgeries.

Across treatment groups, 60.1% to 70.9% of study eyes had a maximum preinjection IOP of
less than 21 mmHg. Comparing ranibizumab 0.5 mg versus sham or PDT treatment, respectively:
39.9% versus 29.1% and 10.9% versus 5.1% had maximum preinjection IOPs of 21 mmHg
or more or 25 mmHg or more, respectively; 44.1% versus 29.9% and 24.2% versus 13.6%
had IOP increases from baseline of 6 mmHg or more or 8 mmHg or more, respectively; 26.1% versus
13.6% and 16.8% versus 9.0% had one or more IOP increase from baseline of 6 mmHg or more
or 8 mmHg or more, respectively, with a concurrent IOP of 21 mmHg or more; 9.6% versus 3.7%
and 7.5% versus 2.4% had one or more IOP increase from baseline of 6 mmHg or more or 8 mmHg
or more, respectively, with a concurrent IOP of 25 mmHg or more. No differences were observed in
fellow eyes.

In conclusion, most ranibizumab-treated eyes did not experience sustained preinjection IOP of 21 mmHg
or more (more than two consecutive visits) over 24 months. When evaluating the combined IOP
endpoint, more ranibizumab-treated
eyes had one or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, with
concurrent highest IOPs of 21 mmHg or more and 25 mmHg or more versus sham or PDT. IOP should
be monitored in eyes receiving ranibizumab.

Role of Posterior
Vitreous Detachment on Outcome of Anti-VEGF Treatment in AMD

The aim of this study was to determine the effect of posterior vitreous detachment on the
outcome of anti-vascular endothelial growth factor (anti-VEGF) injection.

A total of 61 eyes with age-related macular degeneration (AMD) that had received
intravitreal bevacizumab or ranibizumab injections were retrospectively reviewed. The
vitreomacular interface was evaluated, and eyes were grouped according to the presence of
posterior vitreous detachment (group one, n=25) or vitreomacular adhesion (group two, n=36).
All patients received three loading doses of intravitreal anti-VEGF injections at monthly intervals,
and subsequently, pro re nata regimen was performed. Best-corrected visual acuity (BCVA)
and central foveal thickness measurement at follow-up were evaluated. The development of
posterior vitreous detachment during the follow-up was also reported.

It was noted that the BCVA changes at each visit compared with baseline were significantly better
in group one (p=0.01, 0.02, 0.02, 0.009, 0.009, respectively at third, sixth, ninth, 12th
month and last visit). When BCVA was classified according to the change in visual acuity of 10
letters or more, the rate of improved or stable BCVA was greater in group one (p=0.02).
During the follow-up, five eyes (14.3%) developed posterior vitreous detachment.

Vitreomacular adhesion seems to have an adverse effect on the visual prognosis of anti-VEGF
treatment for AMD.

Scientists sought to compare the sensitivity of commonly used time-domain optical
coherence tomography (TD-OCT) and spectral-domain OCT (SD-OCT) platforms and scanning
modalities in the management of neovascular age-related macular degeneration (AMD) in
a population with a high prevalence of exudative disease activity.

In this neovascular AMD patient population, SD-OCT was a superior diagnostic tool when compared
with TD-OCT, with each spectral-domain platform and acquisition setting identifying significantly
more exudative disease activity. The scientists did not directly compare the two
spectral-domain platforms (Cirrus and Spectralis) because identical image acquisition parameters
were not used. No individual imaging modality demonstrated a diagnostic advantage for
detecting subretinal fluid versus intraretinal cysts.

They assigned eyes to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a two-year
monthly or pro re nata (p.r.n.) injection regimen, or monthly injections for one year and
p.r.n. for one year. They evaluated demographic, genetic and baseline ocular characteristics and
lesion features of CFP/FA and optical coherence tomography (OCT) as risk factors for GA through
two years of follow-up. The authors also used time-dependent Cox proportional hazard models to
estimate adjusted hazard ratios (aHRs). Development of GA was the main outcome measure.

They determined that approximately one-fifth of CATT patients developed GA within two years
of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal
fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor
therapy may have a role in the development of GA.

Change in Drusen Volume as a
Novel Clinical Trial Endpoint for the Study of Complement Inhibition in AMD

In the following single-center, prospective, randomized, double-masked clinical
trial, researchers evaluated the change in drusen volume following treatment with eculizumab,
a systemic inhibitor of complement component 5.

They randomized patients 2:1 to receive intravenous eculizumab or placebo over 26 weeks. The
main outcome measure was a decrease in drusen volume of at least 50% at 26-week follow-up.

The researchers reported that mean drusen cube root volumes were 0.49 mm and 0.47 mm (p=0.64)
at baseline and 0.51 mm and 0.42 mm (p=0.17) at 26 weeks in the eculizumab and placebo
groups, respectively. They also found that in the placebo group, one eye had a decrease in drusen
volume of at least 50% and two eyes developed neovascularization through 26 weeks.

To conclude, systemic complement inhibition with eculizumab did not significantly reduce drusen
volume. Drusen growth was dependent on the number of complement at-risk alleles. Future trials
should consider the use of a composite clinical trial endpoint in which efficacy is defined by
the treatment's ability to prevent drusen growth, neovascularization and the formation of
geographic atrophy over one year.

Providing long-term follow-up of the natural history of age-related macular
degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and
clinical trials. In this study, investigators aimed to describe 10-year progression rates
to intermediate or advanced AMD.

They observed the Age-Related Eye Disease Study (AREDS) participants for an additional five years
after a randomized clinical trial of antioxidant vitamins and minerals was completed.
Observation occurred at 11 clinical sites of medical retinal practices from academic institutions
and community medical centers. The study investigators followed participants aged 55 to 80 years
with no AMD or AMD of varying severity (n=4,757) up in the AREDS trial for a median duration of
6.5 years. When the trial ended, they followed 3,549 of the 4,203 surviving participants for
five additional years. Exposure was defined as treatment with antioxidant vitamins and minerals.

Development of varying stages of AMD and changes in visual acuity were the main outcome measures.
The investigators evaluated the rates of progression to large drusen and advanced AMD (neovascular
AMD or central geographic atrophy [GA]) using annual fundus photographs assessed centrally. They
also measured best-corrected visual acuity at annual study visits.

They found that the risk of progression to advanced AMD increased with increasing age
(p=0.01) and severity of drusen. They also noted that women (p=0.005) and current
smokers (p<0.001) were at increased risk of neovascular AMD. In the oldest participants
with the most severe AMD status at baseline, the risks of developing neovascular AMD and central
GA by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to
large drusen increased with increasing severity of drusen at baseline, with 70.9% of
participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced
AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but
never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity
of 20/200.

The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced
AMD. These progression data and the risk factor analyses may be helpful to investigators
conducting research in clinic populations.

Relationship Between
Polymorphism of the DNA Repair SMUG1 and UNG Genes and AMD

The authors of the following study investigated the association between the g.4235T>C
(rs2337395) polymorphism of the UNG gene and the c.–31A>G (rs3087404) polymorphism of the
SMUG1 gene and the risk of age-related macular degeneration (AMD), as well as modulation of
this association by some environmental and lifestyle factors.

They enrolled 272 AMD patients and 105 control subjects in this study, and genotyped both
polymorphisms by restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP).

The study authors reported that C/C genotype of the g.4235T>C polymorphism of the UNG gene
was associated with an increased risk of dry AMD (odds ratio, 2.54), whereas the T/T genotype of
this polymorphism decreased such risk (odds ratio, 0.41). They noted that the presence of the T
allele of the g.4235T>C polymorphism and the A allele of the c.–31A>G polymorphism
of the SMUG1 gene (odds ratio, 2.17 and 2.18, respectively) was associated with an increased risk
of AMD severity, expressed by the comparison of the frequencies of genotypes in the group of
patients with wet AMD versus those with dry AMD. Conversely, the C/C genotype of the
g.4235T>C polymorphism, the G/G genotype of the c.–31A>G polymorphism, and the
C/C-G/G combined genotype of both polymorphisms had a protective effect (odds ratio, 0.48, 0.46,
and 0.18; respectively).

In conclusion, the results obtained suggest the potential role of the g.4235T>C and the
c.–31A>G polymorphisms in AMD pathogenesis.

It included 49 eyes with the new onset diabetic CME that had to have a macular SD-OCT and
fluorescein angiography at presentation. The baseline OCT scans were analyzed for variables
indicative of the extent of retinal involvement by the cystoid change and its location about the
center. Univariate and multivariate analyses were performed comparing the OCT findings between the
two groups of eyes: the “no improvement” and the “improvement” groups,
based on at least two Snellen lines improvement after treatment.

There were 30 and 19 eyes in the no improvement and improvement groups, respectively. In the
univariate analysis, the baseline OCT parameters associated with visual improvement included
the photoreceptor inner segments thickness centrally (p=0.009) and within the central
1-mm subfield (p<0.0001), and the presence of bridging retinal processes centrally
(p=0.004). Multivariate analysis showed both presence and central location of bridging
retinal processes within the central 1-mm subfield to be significantly associated with
visual improvement (p=0.041 and 0.005, respectively), with an odds ratio of 13.4
(95% confidence interval, 1.336-636.18; p=0.010) for their central location.

In diabetic CME, visual improvement after anti-VEGF therapy is more likely to occur in eyes
with residual central retinal processes on baseline macular SD-OCT. This finding may be helpful
in patient counseling, case selection and clinical trial planning.

The researchers noted that the groups did not differ in baseline BCVA, central subfield thickness
and total macular volume. They also reported that compared with the ranibizumab injection group,
the sham group had significantly larger central subfield thickness increases relative to baseline
at one week and one month; larger total macular volume increases at all time points (p=0.012,
p=0.005, p<0.001, p<0.001, p=0.005, p=0.017,
respectively); higher PME frequency at one month (p=0.019); and poorer BCVA improvement
from baseline to six months after surgery (p=0.046).

In conclusion, in patients with stable diabetic retinopathy without significant macular
edema, intravitreal ranibizumab injection at cataract surgery may prevent the postoperative
worsening of macular edema and may improve the final visual outcome without affecting safety.

A total of 177 treatment-naïve patients with macular edema secondary to CRVO were randomized in
a 3:2 ratio. Patients received either 2-mg intravitreal aflibercept or sham injections every four
weeks for 20 weeks. From week 24 to 48, the aflibercept group received aflibercept as needed
(pro re nata [p.r.n.]), and the sham group continued receiving sham injections. The
primary efficacy endpoint was the proportion of patients who gained 15 letters or more in
best-corrected visual acuity (BCVA) at week 24. This study reports week 52 results including
the proportion of patients who gained 15 letters or more in BCVA and the mean change from baseline
BCVA and central retinal thickness. Efficacy end points at week 52 were all exploratory.

At week 52, the mean percentage of patients gaining 15 letters or more was 60.2% in the
aflibercept group and 32.4% in the sham group (p=0.0004). Aflibercept patients,
compared with sham patients, had a significantly higher mean improvement in BCVA (+16.9 letters vs.
+3.8 letters, respectively) and reduction in central retinal thickness (–423.5 µm vs.
–219.3 µm, respectively) at week 52 (p<0.0001 for both). Aflibercept
patients received a mean of 2.5 injections (standard deviation, 1.7 injections) during p.r.n.
dosing. The most common ocular adverse events in the aflibercept group were related to the
injection procedure or the underlying disease, and included macular edema (33.7%),
increased intraocular pressure (17.3%) and eye pain (14.4%).

To conclude, treatment with intravitreal aflibercept provided significant functional and
anatomic benefits after 52 weeks as compared with sham. The improvements achieved after six
monthly doses at week 24 largely were maintained until week 52 with as-needed dosing.
Intravitreal aflibercept generally was well-tolerated.

Scientists recruited 36 patients from five institutions to assess the efficacy of intravitreal
0.5 mg ranibizumab for the treatment of center-involving macular edema secondary to branch retinal
vein occlusion (BRVO) over one year compared with standard-of-care grid laser.

In this prospective, randomized controlled clinical trial, patients with vision loss in one
eye attributable to macular edema following BRVO were randomized 1:1 to a treatment group that
received six monthly injections of 0.5 mg ranibizumab and thereafter monthly as needed based
on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) assessments on
optical coherence tomography scans or a standard-of-care group that received monthly sham injections
for the one-year duration of the study. The scientists administered grid laser at 13 and 25 weeks
in both groups if criteria for laser treatment were met. Main outcome measures included mean change
in BCVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores from baseline to
month 12. Secondary outcomes included anatomic outcomes and the percentage of patients requiring
grid laser in both groups.

According to the study scientists, mean BCVA change from baseline was significantly greater in
the treatment compared with the standard-of-care group at 12 months (12.5 ETDRS letters vs.
–1.6 ETDRS letters, p=0.032). The mean CFT was significantly reduced in the
treatment compared with standard-of-care group (361.7 µm vs. 175.6 µm, p=0.025).
At 13 and 25 weeks, more patients in the standard-of-care group (68.4%, 50.0%) received
grid laser than in the treatment group (6.7%, 8.3%). No new ocular or systemic adverse
events were observed.

To determine long-term outcomes of patients with ranibizumab-treated retinal vein occlusion (RVO),
the authors of this prospective follow-up of a subset of patients from two Phase III trials looked at
34 patients with branch RVO (BRVO) and 32 with central RVO (CRVO) who completed the
Genentech-sponsored ranibizumab study RVO trials.

Patients seen every month in year one and at least every three months in year two were treated
with ranibizumab for intraretinal fluid. Patients requiring injections on consecutive visits
were treated with ranibizumab plus scatter photocoagulation. The main outcome measure was
mean improvement in best-corrected visual acuity (BCVA) and percentage of patients with
edema resolution.

With a mean follow-up of 49.0 months, 17 of 34 BRVO patients (50%) had edema resolution defined
as no intraretinal fluid for six months or more after the last injection. According to the
study authors, the last injection was given within two years of treatment initiation in 76%.
They also noted that the mean number of injections required in unresolved patients in year four
was 3.2. In patients with resolved edema, mean improvement in BCVA was 25.9 letters versus 17.1
letters (p=0.09) in unresolved patients, and in both groups, approximately 80% had a
final BCVA of 20/40 or better, the authors reported. With a mean follow-up of 49.7 months, 14 of 32
CRVO patients (44%) had edema resolution, with 71% receiving their last injection within
two years of treatment initiation. The mean number of injections in unresolved patients in year four
was 5.9. Compared with patients with unresolved CRVO, patients with resolved disease had
greater improvement in BCVA (25.2 vs. 4.3 letters; p=0.002), and a greater percentage had
a final BCVA of 20/40 or better (64.3% vs. 27.8%; p=0.04). Nine patients with BRVO
and nine with CRVO received scatter photocoagulation, and with mean follow-up of nine months (BRVO)
and 11 months (CRVO) after last laser, only one in each group had resolution of edema.

Long-term outcomes in BRVO patients treated with ranibizumab were excellent, and although half
still required occasional injections after four years, they maintained good visual potential.
The authors of this study determined that a substantial minority (44%) of patients
with ranibizumab-treated CRVO had edema resolution and a good outcome within four years, but most
(56%) still required frequent injections, had reduced visual potential, and have a
guarded prognosis.

To study the anatomical outcome of rhegmatogenous retinal detachment combined with choroidal
detachment after pars plana vitrectomy with periocular/intravitreal injection of steroids,
investigators treated 77 eyes that have rhegmatogenous retinal detachment combined with
choroidal detachment by pars plana vitrectomy with oral prednisolone (group A)
or periocular/intravitreal injection of steroids (group B). They then divided eyes into five
subgroups according to different intraocular tamponade agents; group A1: oral steroids and silicone
oil; group A2: oral steroids and C3F8; group B1: periocular/intravitreal
steroid injections and silicone oil; group B2: periocular steroid injection and silicone oil, and
group B3: periocular steroid injection and C3F8. They measured
anatomical reattachment of the retina at 12 months after surgery.

The study investigators found no significant difference in retinal reattachment rate between
eyes in group A and eyes in group B (77.4% vs. 73.9%, p=0.726). The retinal
reattachment rates were 83.3% in group A1, 69.2% in group A2, 82.4% in group B1,
73.3% in group B2, and 64.3% in group B3. There was no statistical difference in the
retinal reattachment rates between any of the groups.

For the treatment of rhegmatogenous retinal detachment combined with choroidal detachment, pars
plana vitrectomy with periocular/intravitreal corticosteroids was comparable in reattachment rate
to pars plana vitrectomy with systemic steroids, suggesting an acceptable alternative for patients
with this condition who cannot tolerate systemic steroids.

Bioheart Inc. announced that it will enroll up to 100 patients in a study to determine
the safety and efficacy of adipose-derived stem cells or AdipoCell in patients with
dry age-related macular degeneration (AMD). The company says that the study has
been reviewed and approved by the Institutional Review Board of the International
Cellular Medicine Society.

Source: Bioheart Inc., December 2013.

Alimera Ships
First Orders of Iluvien to U.K. National Health Service Hospitals

pSivida Corp.'s licensee Alimera Sciences has shipped initial orders of Iluvien
to several U.K. National Health Service (NHS) facilities. The company also noted that
the first NHS patient has received Iluvien for the treatment of chronic macular edema
(DME) insufficiently responsive to available therapies. In November, the National
Institute for Health and Care Excellence published final guidance recommending Iluvien
as a treatment option for pseudophakic patients with chronic DME insufficiently
responsive to available therapies, subject to a patient access scheme.

Source: pSivida Corp., January 2014.

Researchers Seek to Characterize Development of
Retinal Detachment After Open Globe Trauma

Researchers from the Massachusetts Eye and Ear, Harvard Vanguard Medical Associates
and Harvard Medical School Department of Ophthalmology have reported on the first
study in 35 years that reviews the circumstances around retinal detachment following
open globe injuries (OGI). The case-control study looked at 892 patients (893 OGIs),
of whom 255 were ultimately diagnosed with retinal detachments, with the remaining
eyes serving as controls. They used Kaplan-Meier analysis to estimate the time
to detachment, and multivariable logistic regression to define the clinical
factors associated with retinal detachment after OGI.

The researchers concluded that retinal detachment is common after open globe trauma, though it
often doesn't appear until days to weeks after the initial traumatic event. Several
clinical variables at the time of initial presentation can predict the future risk of
detachment. Additionally, the study researchers created a new screening tool: the Retinal
Detachment after Open Globe Injury score. For additional details on the study, click here.

A team of researchers has created an ultra high-speed, handheld swept-source
optical coherence tomography ophthalmic imaging instrument using a
2-D micro-electro-mechanical systems (MEMS) mirror to enable screening applications
to identify early retinal disease before irreversible vision impairment or loss occurs.
The device scans a patient's retina in seconds and corrects for movement by
averaging and registering 25 B-scans obtained over the same position in 0.57 seconds.
Check out the
paper
published by the researchers in Biomedical Optics Express.